This invention relates to the fields of pharmaceutical and organic chemistry and provides novel acrylic and propionic acid compounds which are useful for the treatment of various medical indications associated with post-menopausal syndrome. The present invention further relates to intermediate compounds and processes useful for preparing the pharmaceutically active compounds. The invention also provides novel methods of treatment and compositions useful in carrying out the methods.
xe2x80x9cPost-menopausal syndromexe2x80x9d is a term used to describe various pathological conditions which frequently affect women who have entered into or completed the physiological metamorphosis known as menopause. Although numerous pathologies are contemplated by the use of this term, two major effects of post-menopausal syndrome are the source of great long-term medical concern: osteoporosis and cardiovascular effects such as hyperlipidemia.
Osteoporosis describes a group of diseases which arise from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate structural support for the body. One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of menses. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women.
There are an estimated 25 million women in the United States, alone, who are afflicted with this disease. The results of osteoporosis are personally harmful and also account for a large economic loss due its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is not generally thought of as a life threatening condition, a 20% to 30% mortality rate is related with hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with post-menopausal osteoporosis.
The most vulnerable tissue in the bone to the effects of post-menopausal osteoporosis is the trabecular bone. This tissue is often referred to as spongy or cancellous bone and is particularly concentrated near the ends of the bone (near the joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which inter-connect with each other, as well as the more solid and dense cortical tissue which makes up the outer surface and central shaft of the bone. This inter-connected network of trabeculae gives lateral support to the outer cortical structure and is critical to the bio-mechanical strength of the overall structure. In post-menopausal osteoporosis, it is, primarily, the net resorption and loss of the trabeculae which leads to the failure and fracture of bone. In light of the loss of the trabeculae in post-menopausal women, it is not surprising that the most common fractures are those associated with bones which are highly dependent on trabecular support, e.g., the vertebrae, the neck of the weight bearing bones such as the femur and the fore-arm. Indeed, hip fracture, collies fractures, and vertebral crush fractures are hall-marks of post-menopausal osteoporosis.
At this time, the only generally accepted method for treatment of post-menopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low primarily because estrogen treatment frequently produces undesirable side effects.
Throughout premenopausal time, most women have less incidence of cardiovascular disease than age-matched men. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen""s ability to regulate the levels of serum lipids. The nature of estrogen""s ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can upregulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
It has been reported in the literature that post-menopausal women having estrogen replacement therapy have a return of serum lipid levels to concentrations to those of the pre-menopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side-effects of estrogen replacement therapy are not acceptable to many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent which would regulate the serum lipid level as does estrogen, but would be devoid of the side-effects and risks associated with estrogen therapy.
In response to the clear need for new pharmaceutical agents which are capable of alleviating the symptoms of post-menopausal syndrome, the present invention provides new acrylic and propionic acid compounds, pharmaceutical compositions thereof, and methods of using such compounds for the treatment of osteoporosis and the cardiovascular effects of post-menopausal syndrome.
The present invention also provides these same acrylic and propionic acid compounds for the treatment of restenosis.
Smooth aortal muscle cell proliferation plays an important role in diseases such as atherosclerosis and restenosis. Vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA) has been shown to be a tissue response characterized by an early and late phase. The early phase occurring hours to days after PTCA is due to thrombosis with some vasospasms while the late phase appears to be dominated by excessive proliferation and migration of aortal smooth muscle cells. In this disease, the increased cell motility and colonization by such muscle cells and macrophages contribute significantly to the pathogenesis of the disease. The excessive proliferation and migration of vascular aortal smooth muscle cells may be the primary mechanism to the reocclusion of coronary arteries following PTCA, atherectomy, laser angioplasty and arterial bypass graft surgery. See xe2x80x9cIntimal Proliferation of Smooth Muscle Cells as an Explanation for Recurrent Coronary Artery Stenosis after Percutaneous Transluminal Coronary Angioplasty,xe2x80x9d Austin et al., Journal of the American College of Cardiology, 8: 369-375 (August 1985).
Vascular restenosis remains a major long term complication following surgical intervention of blocked arteries by percutaneous transluminal coronary angioplasty (PTCA), atherectomy, laser angioplasty and arterial bypass graft surgery. In about 35% of the patients who undergo PTCA, reocclusion occurs within three to six months after the procedure. The current strategies for treating vascular restenosis include mechanical intervention by devices such as stents or pharmacologic therapies including heparin, low molecular weight heparin, coumarin, aspirin, fish oil, calcium antagonist, steroids, and prostacyclin. These strategies have failed to curb the reocclusion rate and have been ineffective for the treatment and prevention of vascular restenosis. See xe2x80x9cPrevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty: The Search for a xe2x80x98Magic Bulletxe2x80x99,xe2x80x9d Hermans et al., American Heart Journal, 122: 171-187 (July 1991).
In the pathogenesis of restenosis, excessive cell proliferation and migration occurs as a result of growth factors produced by cellular constituents in the blood and the damaged arterial vessel wall which mediate the proliferation of smooth muscle cells in vascular restenosis.
Agents that inhibit the proliferation and/or migration of smooth aortal muscle cells are useful in the treatment and prevention of restenosis. The present invention provides for the use of compounds as smooth aortal muscle cell proliferation inhibitors and, thus inhibitors of restenosis.
The present invention relates to compounds of Formula I: 
wherein
each of R and R1 is independently hydrogen, hydroxy, C1-C4-alkoxy, benzyloxy, C1-C6-alkanoyloxy, benzoyloxy, substituted benzoyloxy bearing 1 to 3 substituents each of which is independently halo, C1-C4-loweralkyl, or C1-C4-loweralkoxy, C1-C5-alkoxycarbonyloxy, or C4-C6-alkylsulfonyloxy;
R3 is xe2x80x94CHxe2x95x90CHxe2x80x94 (trans) or xe2x80x94CH2xe2x80x94CH2xe2x80x94;
R4 is hydroxy, C1-C4-alkoxy, or xe2x80x94N(R5)2 wherein each
R5 is taken separately and independently represents hydrogen or Cl-C6-alkyl, or both R5 are taken with the N atom and constitute pyrrolidino, piperidino, hexamethyleneimino, or morpholino; or a pharmaceutically acceptable salt thereof.
Preferred compounds are those wherein
R3=xe2x80x94CHxe2x95x90CHxe2x80x94 (trans);
R4=xe2x80x94OH (including salts) or xe2x80x94OEt ; or
R and R1=OH or OCH3.
Compounds embodying multiple preferences, in any combination, are also preferred.
Also provided by the present invention are intermediate compounds of Formula Ia, which are useful for preparing the pharmaceutically active compounds of the present invention, and which are shown below 
wherein each of Ra and R1a is independently hydrogen, C1-C4-alkoxy, benzyloxy, C2-C6-alkanoyloxy, benzoyloxy, substituted benzoyloxy bearing 1 to 3 substituents each of which is independently halo, C1-C4-loweralkyl, or C1-C4-loweralkoxy, C1-5-alkoxycarbonyloxy, or C4-C6-alkylsulfonyloxy.
The present invention further relates to pharmaceutical compositions containing compounds of Formula I, optionally containing estrogen or progestin, and the use of such compounds, alone, or in combination with estrogen or progestin, for alleviating the symptoms of post-menopausal syndrome, particularly osteoporosis and cardiovascular related pathological conditions.
The compounds of the present invention also are expected to be useful in inhibiting aortal smooth muscle cell proliferation, particularly restenosis, in humans.
Most of the compounds of Formula I are made by conversion of the formylbenzoyl compounds of Formula Ia: 
This conversion is an example of a Horner-Emmons reaction, which is discussed in detail by Wadsworth in Organic Reactions, 1977, 25, 73-253, which is incorporated herein by reference.
The conversion of the p-formylbenzoyl compounds is achieved by reacting a compound of Formula Ia with the carbanion of a trialkyl phosphonoacetate. This carbanion is generated by pretreating the trialkyl phosphonoacetate with a strong base, such as n-butyllithium, sodium hydride, and DBU. The reaction is conducted in an inert solvent; suitable such solvents include tetrahydrofuran, dioxane, benzene, 1,2-dimethoxyethane, and diethyl ether. The reaction is conducted at temperatures of from xe2x88x9278xc2x0 to 0xc2x0. The amounts of the reactants are not critical; the reaction consumes equimolar amounts of the p-formylbenzoyl compound and the trialkyl phosphonoacetate carbanion. The product is isolated from the reaction mixture in conventional manner.
In Formula Ia, Ra and R1a represent any of the groups defined for R and R1 exclusive of hydroxy. This reaction is conducted with any hydroxy group having first been protected. Hydroxy protection is well known; see, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973); Protecting Groups in Organic Synthesis, Wiley (New York, 1981); and The Peptides, Vol. I, Schrooder and Lubke, Academic Press (London and New York, 1965). Hydroxyl protection is also discussed in U.S. Pat. No. 4,418,068, which is incorporated herein by reference. The following R and R1 groups are in the nature of hydroxy protecting groups: C1-C4-alkoxy, benzyloxy, C1-C6-alkanoyloxy, benzoyloxy, substituted benzoyloxy bearing 1 to 3 substituents each of which is independently halo, C1-C4-loweralkyl, or C1-C4-loweralkoxy, C1-C5-alkoxycarbonyloxy, and C4-C6-alkylsulfonyloxy. These compounds are primarily useful as chemical intermediates, but some of them exhibit useful biological activity in addition.
Other compounds of the present invention are prepared in standard manners well known to those skilled in the art. The free acids (R4=OH) are prepared by hydrolysis; the resulting acids can be reacted subsequently with alkanols to form other esters, or with amines to form the amides. Deprotection of the hydroxy protecting groups is done by well known procedures, which are discussed in the reference cited above. Hydrogenation of the R3=xe2x80x94CHxe2x95x90CHxe2x80x94 compounds yields the corresponding R3=xe2x80x94CH2xe2x80x94CH2xe2x80x94 compounds.
Therefore, in one embodiment the present invention is directed to a method of preparing a compound of Formula Ib. 
wherein each of Ra and R1a is independently hydrogen, C1-C4-alkoxy, benzyloxy, C2-C6-alkanoyloxy, benzoyloxy, substituted benzoyloxy bearing 1 to 3 substituents each of which is independently halo, C1-C4-loweralkyl, or C1-C4-loweralkoxy, C1-5-alkoxycarbonyloxy, or C4-C6-alkylsulfonyloxy;
R3a is xe2x80x94CHxe2x95x90CHxe2x80x94 (trans); and
R4a is C1-C4-alkoxy, which comprises reacting a compound of Formula Ia 
with a trialkyl phosphonoacetate carbanion in an inert solvent at a temperature from xe2x88x9278xc2x0 to 0xc2x0. Optionally, any one or more additional reactions are thereafter conducted:
hydrolyzing the ester to an acid,
removing hydroxy protecting groups,
hydrogenating CHxe2x95x90CH to CH2xe2x80x94CH2, and
converting the acid to an ester, amide, or salt.
The present compounds can be used for the purposes described herein in the free-acid form (R4=hydroxy). However, it is feasible and sometimes preferred to use pharmaceutically acceptable salts, such as an ammonium salt; or an inorganic alkali metal salt, e.g., sodium or potassium, or an organic amine salt such as methylamine, diethylamine, triethylamine, pyridine, morpholine, n-butylamine, and octadecylamine. The preparation of such salts is well known. Typically the compound of Formula I is reacted with an equimolar or excess amount of base. The reactants are generally combined in a mutual inert solvent; the salt normally precipitates out of solution and can be isolated by filtration, or the solvent can be removed by conventional means.
The p-formylbenzoyl compounds, Formula Ia, represent another embodiment of the present invention. They are prepared by the following reaction scheme: 
which is more fully illustrated by Preparations 1-3, below. The benzo[b]thiophenes which are employed as starting materials are prepared as described in U.S. Pat. Nos. 4,418,068 and 4,133,814, which are incorporated herein by reference. The latter of these also describes the preparation of the 1-carboxy-2-phenylbenzo[b]thiophenes, by another route than above.

To a solution of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (27.0 g, 100 mmol) in 1.10 L of CHCl3 at 60xc2x0 C. was added bromine (15.98 g, 100 mmol) dropwise as a solution in 200 mL of CHCl3. After the addition was complete, the reaction was cooled to room temperature, and the solvent removed in vacuo to provide 34.2 g (100%) of 6-methoxy-2-(4-methoxyphenyl)-3-bromobenzo[b]thiophene as a white solid. mp 83-85xc2x0 C. 1H NMR (DMSO-d6) xcex47.70-7.62 (m, 4H), 7.17 (dd, J=8.6, 2.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H). FD mass spec: 349, 350. Anal. Calcd. for C16H13O2SBr: C, 55.03; H, 3.75. Found: C, 54.79; H, 3.76.

6-Methoxy-2-(4-methoxyphenyl)-3-bromobenzo[b]thiophene (15.0 g, 42.9 mmol) was dissolved in 300 mL of anhydrous THF under N2 and cooled to xe2x88x9270xc2x0 C. To this solution was added nBuLi (29.6 mL, 47.4 mmol, 1.6 M solution in hexanes) dropwise via syringe. After stirring at xe2x88x9270xc2x0 C. for 20 min, a steady stream of CO2 (g) was introduced into the reaction mixture for 15 min. The mixture was allowed to gradually warm to 0xc2x0 C. and then quenched by pouring the mixture into cold 1 N HCl (500 mL). The aqueous layer was extracted with EtOAc (3xc3x97300 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to a solid. The crude product was chromatographed (SiO2, 25% EtOAc/hexanes) to provide 9.35 g (69%) of 6-methoxy-2-(4-methoxyphenyl)-3-carboxybenzo[b]thiophene as a white solid. mp 166-170xc2x0 C. 1H NMR (DMSO-d6) xcex4 (doubling due to rotamers) 13.0-12.8 (bs), 8.10 and 7.68 (d, J=8.1 Hz, 1H), 7.63 and 7.47 (d, J=8.6 Hz, 2H), 7.59 and 7.54 (d, J=2.0 Hz, 1H), 7.10 and 6.97 (dd, J=8.1, 2.0 Hz, 1H), 7.02 (d, J=8.6 Hz, 2H), 3.83 and 3.79 (s, 3H), 3.82 and 3.80 (s, 3H). FD mass spec: 315. Anal. Calcd. for C17H14O4S: C, 64.95; H, 4.49. Found: C, 65.19; H, 4.32.

To a solution of 6-methoxy-2-(4-methoxyphenyl)-3-carboxybenzo[b]thiophene (4.00 g, 12.74 mmol) in 100 mL of anhydrous CH2Cl2 was added thionyl chloride (3.0 mL, 38.22 mmol) along with 0.1 mL of DMF. The resulting mixture was heated to reflux for 5 h. Upon cooling, the solvent and excess thionyl chloride were removed in vacuo to give the acid chloride as a yellow oil. The acid chloride was then dissolved in 75 mL of THF under N2.
In a separate flask, 4-bromobenzaldehyde diethyl acetal (3.65 g, 14.0 mmol) was dissolved in 50 mL of anhydrous THF under N2 and cooled to xe2x88x9278xc2x0 C. To this solution was added nBuLi (8.,76 mL, 14.0 mmol, 1.6 M solution in hexanes) dropwise via syringe. After stirring for 20 min at xe2x88x9278xc2x0 C., the solution was transferred via cannula to a xe2x88x9278xc2x0 C. solution of the acid chloride. The resulting mixture was allowed to gradually warm to room temperature, and then quenched by pouring into cold 0.2 N NaOH (200 mL). The aqueous was extracted with EtOAc (2xc3x97200 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give crude 6-methoxy-3-[(4-diethoxymethyl)benzoyl]-2-(4-methoxyphenyl)benzo[b ]thiophene as a yellow oil. This material was immediately dissolved in 200 mL of reagent grade acetone, and pTsOH (150 mg) was added. After stirring for 30 min at room temperature, TLC indicated that the diethyl acetal had been converted to aldehyde. The reaction was quenched by the addition of anhydrous K2CO3 (500 mg). After removal of the solids by filtration, the filtrate was concentrated in vacuo to a dark oil that was chromatographed (SiO2, hexanes/EtOAc) to provide 1.70 g (33%) of 6-methoxy-3-(4-formylbenzoyl-2-(4-methoxyphenyl)benzo[b]thiophene as a yellow solid. mp 147-150xc2x0 C. 1H NMR (DMSO-d6) xcex410.03 (s, 1H), 7.85 (s, 4H), 7.70 (d, J=2.2 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.28 (d, J=9.0 Hz, 2H), 7.06 (dd, J=9.0, 2.2 Hz, 1H), 6.84 (d, J=9.0 Hz, 2H), 3.67 (s, 3H), 3.86 (s, 3H). FD mass spec: 402.